The innate immune system comprises several classes of pattern recognition receptors, including Toll- like receptors (TLRs) and NOD-like receptors (NLRs). A set of NLR family members form a multi-protein complex termed 'the inflammasome', which contains the adaptor protein ASC and caspase-1, and promotes caspase-1 activation and maturation of IL-1 and IL-18, the secretion of which leads to a potent inflammatory response. Caspase-1 is the prototypical member of the inflammatory caspases and is a key target in several inflammatory, infectious and autoimmune diseases. Studies show that caspase-1-deficient mice are resistant to the toxic effects of lipopolysaccharide, Escherichia coli-induced shock, and apoptotic cell death. Interestingly, IL-1 and IL-18, the two major downstream target molecules of caspase-1 are not involved suggesting that some other downstream targets of caspase-1 are important. Additionally, our studies show that the commonly used lines of caspase-1-deficient mice are also deficient in caspase-11 suggesting that the inflammatory functions attributed to caspase-1 could be the combined actions of both caspase-1 and caspase-11. This proposal will address the central hypothesis that NLR/caspase-1 and caspase-11 signaling axis plays a crucial role in innate immunity to microbial pathogens. We identified several important caspase-1 substrates in a proteome-wide screen and our preliminary data suggest a key role for a set of these substrates in inflammation and sepsis induction. Overall, this study will elucidate the roles of caspase-1 and caspase-11 and their effector mechanisms in innate immunity and inflammation and will help identify the molecular and cellular mechanisms regulating innate immunity and inflammation, thus leading to novel therapeutic targets for inflammatory and infectious diseases.